Friday, May 17, 2024
5/17/2024
Project Summary/Abstract Treating retinal degenerative diseases has been hampered by the lack of suitable systems that can evaluate how new treatment strategies affect the function of the human retina. Human stem cell-derived 3- dimensional retinal organoid technologies have been recently developed. Remarkably, human retinal organoids mimic the native tissue's histological organization, cellular composition, and are able to respond to light. These organoids are an ideal model system for investigating novel therapies to treat blinding diseases. However, to fully realize the unprecedented potential of human retinal organoids for the development of treatments for retinal degenerative diseases, we need new technologies that can rapidly measure retinal function under a wide variety of conditions. Current techniques such as patch-clamp electrophysiology, calcium imaging, and multi-electrode array recordings, measure how individual cells function within the circuitry of the retina. However, these techniques are laborious and ineffective at assessing the health, reproducibility, and functional responsivity of the retina as a whole - features that are key to the application of organoid systems to drug screening and validation. The lack of a device and techniques that allow for rapid, non-invasive screening of the functional status of retinal organoids constitutes a major unmet need. In Aim 1 of this proposal, we will develop an electroretinogram (ERG) recording chamber and a recording protocol for real-time assessment of light-evoked retinal organoid physiology by measuring photoreceptor and bipolar cell function. Our findings will be used to establish critical metrics associated with normal organoid light-evoked responsivity. Further, we will evaluate the power of this approach to detect changes in photoreceptor function, to provide evidence of its applicability to the assessment of disease models and therapeutic screening. To take full advantage of this technology for downstream applications it is critical that it be combined with robust organoid models. The variability and low yield of current protocols for retinal organoid generation and the extended time required for functional maturation of organoid photoreceptors hinder their application in drug development and disease evaluation. In Aim 2 of this proposal, we will address this critical gap by developing and evaluating improved protocols for human retinal organoid generation that increase yield and accelerate photoreceptor differentiation. We will then evaluate retinal function in these improved organoids using our ERG platform. Through the combination of these technologies, we will have created the first system for rapid, non- invasive functional screening in human retinal organoids that can be applied to the evaluation of normal, diseased, and drug-treated conditions. Our system has the potential to greatly accelerate the development of novel therapies to reverse vision loss.
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